Synergistic therapy for pancreatic cancer by deactivating cancer-associated fibroblasts and driving T-cell migration into tumor microenvironment using nanochaperone delivery system
The success of immunotherapy in pancreatic ductal adenocarcinoma (PDAC) is greatly limited by the scarcity of cytotoxic T lymphocytes (CTLs) in tumor microenvironment, which is mainly due to the physical barrier formed by a dense extracellular matrix (ECM). Here we reported a potent strategy to rect...
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KeAi Communications Co., Ltd.
2025-10-01
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| Series: | Bioactive Materials |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2452199X25002397 |
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| author | Jiajing Chen Feihe Ma Yujie Chen Mengchen Xu Yongxin Zhang Shuyu Wang Hongyun Liu Linlin Xu Yang Liu Rujiang Ma Jinpu Yu Linqi Shi |
| author_facet | Jiajing Chen Feihe Ma Yujie Chen Mengchen Xu Yongxin Zhang Shuyu Wang Hongyun Liu Linlin Xu Yang Liu Rujiang Ma Jinpu Yu Linqi Shi |
| author_sort | Jiajing Chen |
| collection | DOAJ |
| description | The success of immunotherapy in pancreatic ductal adenocarcinoma (PDAC) is greatly limited by the scarcity of cytotoxic T lymphocytes (CTLs) in tumor microenvironment, which is mainly due to the physical barrier formed by a dense extracellular matrix (ECM). Here we reported a potent strategy to rectify the CTLs infiltration in PDAC by synergistically deactivating cancer-associated fibroblasts (CAFs) and driving T-Cell migration into tumor microenvironment. This combination therapy is achieved by co-delivery of vitamin D receptor ligand (calcipotriol, Cal) and chemokine (CXCL9) using nanochaperone (nChap) delivery platform. We demonstrate that Cal reverses the activated CAFs to quiescence for resulting in a loosened ECM, while the CXCL9 gradient increases the recruitment signal of CD8+ T cells, synergistically enhancing the intratumoral infiltration of CD8+ T cells. Noteworthily, this system (Cal@nChap-CXCL9) promotes both the penetration of immunotherapeutic (anti-PD-1) and chemotherapeutic (gemcitabine), significantly enhancing the efficacy of chemo-immunotherapy for advanced large Panc02 tumors. This study provides a promising strategy for enhanced PDAC immunotherapy. |
| format | Article |
| id | doaj-art-b9651f0bc05343db8592d118755951bc |
| institution | Kabale University |
| issn | 2452-199X |
| language | English |
| publishDate | 2025-10-01 |
| publisher | KeAi Communications Co., Ltd. |
| record_format | Article |
| series | Bioactive Materials |
| spelling | doaj-art-b9651f0bc05343db8592d118755951bc2025-08-24T05:13:43ZengKeAi Communications Co., Ltd.Bioactive Materials2452-199X2025-10-015228729910.1016/j.bioactmat.2025.06.010Synergistic therapy for pancreatic cancer by deactivating cancer-associated fibroblasts and driving T-cell migration into tumor microenvironment using nanochaperone delivery systemJiajing Chen0Feihe Ma1Yujie Chen2Mengchen Xu3Yongxin Zhang4Shuyu Wang5Hongyun Liu6Linlin Xu7Yang Liu8Rujiang Ma9Jinpu Yu10Linqi Shi11Tianjin Key Laboratory of Extracorporeal Life Support for Critical Diseases, Tianjin Institute of Hepatobiliary Disease, The Third Central Hospital of Tianjin, Tianjin, 300170, ChinaKey Laboratory of Functional Polymer Materials of Ministry of Education, Institute of Polymer Chemistry, Tianjin Key Laboratory of Functional Polymer Materials, State Key Laboratory of Medicinal Chemical Biology, Frontiers Science Center for New Organic Matter, College of Chemistry, Nankai University, Tianjin, 300071, China; Corresponding author.Key Laboratory of Functional Polymer Materials of Ministry of Education, Institute of Polymer Chemistry, Tianjin Key Laboratory of Functional Polymer Materials, State Key Laboratory of Medicinal Chemical Biology, Frontiers Science Center for New Organic Matter, College of Chemistry, Nankai University, Tianjin, 300071, ChinaKey Laboratory of Functional Polymer Materials of Ministry of Education, Institute of Polymer Chemistry, Tianjin Key Laboratory of Functional Polymer Materials, State Key Laboratory of Medicinal Chemical Biology, Frontiers Science Center for New Organic Matter, College of Chemistry, Nankai University, Tianjin, 300071, ChinaKey Laboratory of Functional Polymer Materials of Ministry of Education, Institute of Polymer Chemistry, Tianjin Key Laboratory of Functional Polymer Materials, State Key Laboratory of Medicinal Chemical Biology, Frontiers Science Center for New Organic Matter, College of Chemistry, Nankai University, Tianjin, 300071, ChinaCancer Molecular Diagnostics Core, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin's Clinical Research Center for Cancer, Tianjin, 300060, ChinaKey Laboratory of Functional Polymer Materials of Ministry of Education, Institute of Polymer Chemistry, Tianjin Key Laboratory of Functional Polymer Materials, State Key Laboratory of Medicinal Chemical Biology, Frontiers Science Center for New Organic Matter, College of Chemistry, Nankai University, Tianjin, 300071, ChinaKey Laboratory of Functional Polymer Materials of Ministry of Education, Institute of Polymer Chemistry, Tianjin Key Laboratory of Functional Polymer Materials, State Key Laboratory of Medicinal Chemical Biology, Frontiers Science Center for New Organic Matter, College of Chemistry, Nankai University, Tianjin, 300071, ChinaKey Laboratory of Functional Polymer Materials of Ministry of Education, Institute of Polymer Chemistry, Tianjin Key Laboratory of Functional Polymer Materials, State Key Laboratory of Medicinal Chemical Biology, Frontiers Science Center for New Organic Matter, College of Chemistry, Nankai University, Tianjin, 300071, ChinaKey Laboratory of Functional Polymer Materials of Ministry of Education, Institute of Polymer Chemistry, Tianjin Key Laboratory of Functional Polymer Materials, State Key Laboratory of Medicinal Chemical Biology, Frontiers Science Center for New Organic Matter, College of Chemistry, Nankai University, Tianjin, 300071, ChinaCancer Molecular Diagnostics Core, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin's Clinical Research Center for Cancer, Tianjin, 300060, China; Corresponding author.Cancer Molecular Diagnostics Core, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin's Clinical Research Center for Cancer, Tianjin, 300060, China; Key Laboratory of Functional Polymer Materials of Ministry of Education, Institute of Polymer Chemistry, Tianjin Key Laboratory of Functional Polymer Materials, State Key Laboratory of Medicinal Chemical Biology, Frontiers Science Center for New Organic Matter, College of Chemistry, Nankai University, Tianjin, 300071, China; Corresponding author. Cancer Molecular Diagnostics Core, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin's Clinical Research Center for Cancer, Tianjin, 300060, China.The success of immunotherapy in pancreatic ductal adenocarcinoma (PDAC) is greatly limited by the scarcity of cytotoxic T lymphocytes (CTLs) in tumor microenvironment, which is mainly due to the physical barrier formed by a dense extracellular matrix (ECM). Here we reported a potent strategy to rectify the CTLs infiltration in PDAC by synergistically deactivating cancer-associated fibroblasts (CAFs) and driving T-Cell migration into tumor microenvironment. This combination therapy is achieved by co-delivery of vitamin D receptor ligand (calcipotriol, Cal) and chemokine (CXCL9) using nanochaperone (nChap) delivery platform. We demonstrate that Cal reverses the activated CAFs to quiescence for resulting in a loosened ECM, while the CXCL9 gradient increases the recruitment signal of CD8+ T cells, synergistically enhancing the intratumoral infiltration of CD8+ T cells. Noteworthily, this system (Cal@nChap-CXCL9) promotes both the penetration of immunotherapeutic (anti-PD-1) and chemotherapeutic (gemcitabine), significantly enhancing the efficacy of chemo-immunotherapy for advanced large Panc02 tumors. This study provides a promising strategy for enhanced PDAC immunotherapy.http://www.sciencedirect.com/science/article/pii/S2452199X25002397Pancreatic cancerChemokinesCancer-associated fibroblastsT cell migrationNanochaperone |
| spellingShingle | Jiajing Chen Feihe Ma Yujie Chen Mengchen Xu Yongxin Zhang Shuyu Wang Hongyun Liu Linlin Xu Yang Liu Rujiang Ma Jinpu Yu Linqi Shi Synergistic therapy for pancreatic cancer by deactivating cancer-associated fibroblasts and driving T-cell migration into tumor microenvironment using nanochaperone delivery system Bioactive Materials Pancreatic cancer Chemokines Cancer-associated fibroblasts T cell migration Nanochaperone |
| title | Synergistic therapy for pancreatic cancer by deactivating cancer-associated fibroblasts and driving T-cell migration into tumor microenvironment using nanochaperone delivery system |
| title_full | Synergistic therapy for pancreatic cancer by deactivating cancer-associated fibroblasts and driving T-cell migration into tumor microenvironment using nanochaperone delivery system |
| title_fullStr | Synergistic therapy for pancreatic cancer by deactivating cancer-associated fibroblasts and driving T-cell migration into tumor microenvironment using nanochaperone delivery system |
| title_full_unstemmed | Synergistic therapy for pancreatic cancer by deactivating cancer-associated fibroblasts and driving T-cell migration into tumor microenvironment using nanochaperone delivery system |
| title_short | Synergistic therapy for pancreatic cancer by deactivating cancer-associated fibroblasts and driving T-cell migration into tumor microenvironment using nanochaperone delivery system |
| title_sort | synergistic therapy for pancreatic cancer by deactivating cancer associated fibroblasts and driving t cell migration into tumor microenvironment using nanochaperone delivery system |
| topic | Pancreatic cancer Chemokines Cancer-associated fibroblasts T cell migration Nanochaperone |
| url | http://www.sciencedirect.com/science/article/pii/S2452199X25002397 |
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